ALBERT

Description: Background Anti-tumor necrosis factor (TNF) therapy has emerged as an effective therapy in inflammatory diseases such as rheumatoid arthritis (RA). One concern is reports of lymphoma development in RA patients receiving such therapy. We performed a population-based and detailed survey of RA and lymphoma characteristics in anti-TNF-treated RA patients with lymphoma. Methods Cross-linkage between the Swedish Biologics Register and the Swedish Cancer Register 1998 through 2006 identified 26 RA patients with lymphoma after start of anti- TNF therapy. The 26 cases correspond to a 3-fold increased risk compared to a general population comparator and a 30% non-significant increased risk compared to anti-TNF-naïve RA patients (Ref 1). The medical records were scrutinized, the lymphoma tissues reclassified, Epstein-Barr virus assessed by EBER in situ hybridization and patients followed-up for survival through March, 2008. Results The patients had longstanding, active RA before start of anti-TNF therapy; mean RA duration 13.9 years and mean number of other disease-modifying anti-rheumatic drugs before anti-TNF therapy 4.5. Treatment response to anti-TNF therapy was poor; 23 of the patients continued to have active RA disease despite anti-TNF therapy. The mean duration of anti-TNF therapy before lymphoma was 28 months (2 weeks-72 months). Six patients had lymphoma diagnosed during the first year after anti-TNF start. Seen in retrospect, 3 of the patients had signs of the lymphoma already before treatment start. Reclassification revealed that 14 patients had aggressive lymphomas (8 diffuse large B-cell lymphoma [31%]), 8 indolent lymphomas and 4 could not be further specified (NHL unspecified). Two of 20 (10%) examined lymphomas were EBV-positive. The main initial symptom of the lymphoma was palpable mass in 8 patients, impaired general health in 3, and the remaining had all different symptoms depending on organ involvement. At diagnosis, 12 patients (46%) had wide-spread lymphoma (Ann Arbor stage IV). Of the 26 patients, 13 had died. The mean survival from diagnosis of lymphoma was 14.7 months. 8 of the patients died within 5 months from diagnosis. Most of the remaining (n=14) had active RA after lymphoma diagnosis/treatment and received specific RA therapy. Lymphoma treatment which included rituximab (n=4) was associated with good RA-response and long duration between start of lymphoma therapy and start of specific RA therapy (mean duration 19 months, min-max: 12–26). The corresponding figure for other lymphoma treatments was 5 months (min-max: 2–9). Conclusion In routine clinical care, a majority of RA patients who developed lymphoma after start of anti-TNF therapy had active RA and poor response to anti-TNF therapy, in line with previous findings of an association between RA disease activity and lymphoma risk (Ref 2). Lymphoma characteristics did not differ from what has been reported in lymphomas in anti-TNF-naïve RA patients (Ref 2). A subgroup of patients had aggressive lymphomas with poor prognosis. Most RA-lymphoma patients surviving first lymphoma treatment experienced relapse of RA. Lymphoma treatment which included rituximab was associated with long periods of improved RA.

Description: Abstract 331 Background and aims: Systemic peripheral T-cell lymphomas (PTCL) are malignancies responding poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by upfront high-dose chemotherapy supported by autologous stem-cell transplantation (HDT/ASCT) in PTCL, the Nordic Lymphoma Group conducted the, so far, largest PTCL-restricted prospective phase II study in previously untreated systemic PTCL. This is the final report of the NLG-T-01 study with a 5-years median follow up. Methods: Patients with previously untreated systemic PTCL aged 18–67 years were included. ALK-positive anaplastic large cell lymphoma (ALCL) cases were excluded. An induction regimen of six cycles of bi-weekly cyclophosphamide, doxorubicin, etoposide, vincristin and prednisone (CHOEP) was given. Age-based (〉60 yrs) omission of etoposide was recommended. If in complete or partial remission, patients received high-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan/cyclophosphamide (BEAM/BEAC) followed by HDT/ASCT. Results: A total of 166 patients with previously untreated PTCL were enrolled. Of these, 160 were histopathologically confirmed and included the following subtypes: PTCL-not otherwise specified (PTCL-NOS) (n=62; 39%), ALK-negative ALCL (n=31; 19%), angioimmunoblastic lymphoma (AIL) (n=30; 19%), enteropathy-associated T-cell lymphoma (n=21; 13%), panniculitis-like (n=6; 4%), T/NK nasal-type (n=5; 3%), and hepatosplenic (n=5; 3%). The M/F ratio was 2.0 and the median age 57 yrs (range 22–67 yrs). The majority of the cases presented with advanced-stage disease (81%), B-symptoms (59%) and elevated s-LDH (62%). Nevertheless, 71% of all patients had a good performance score (PS) (WHO 0–1) at inclusion. With regard to the International Prognostic Index (IPI), risk factor distribution was as follows: 1 factor n=45 (28%), 2 factors n=52 (32%), 3 factors n=30 (19%), 4–5 factors n=33 (21%). Of the 160 patients, a total of 114 (71%) underwent HDT/ASCT with 90 in complete remission at 3 months post-transplant. Early failures occurred in 26% of the patients. The treatment related mortality was low (4%). At a median follow-up of 60 months, 83 patients were alive. The median follow-up for deceased patients (N=77) was 9 months. The consolidated 5-yr overall (OS) and progression-free survival (PFS) values for the entire cohort were 51% and 44%, respectively. Best results were obtained in ALK-negative ALCL with 5-yr OS and PFS of 70% and 61%, respectively. IPI was a useful overall prognostic discriminator for the low/low-intermediate vs. intermediate-high/high groups with regard to 5-yr OS (p=0,047) and 5-yr PFS (p=0,029). If applied separately to each of the four major subtypes, IPI had a predictive value for OS in AIL (p=0,02) and for PFS in both AIL (p=0,02) and PTCL-NOS (p=0,03). The clinicopathological parameters that showed a significant impact on OS and PFS were: female gender (correlated with a better outcome), age (analyzed as continuous variable), PS≥2 (correlated with adverse outcome), and cytotoxic phenotype (correlated with adverse outcome in AIL). All these parameters retained their prognostic value at multivariate level, except for cytotoxic phenotype, where multivariate analysis could not be performed because of too small numbers. Conclusions: Dose-dense induction followed by HDT/ASCT is well tolerated and leads to long-term PFS in 44% of patients with systemic PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the present study population. Therefore, based on these results, dose-dense induction and HDT/ASCT should be considered in transplant-eligible PTCL patients. Disclosures: Jantunen: Genzyme: Honoraria.

Description: The immunoglobulin variable heavy chain (IgVH) gene mutation status is an important prognostic factor in chronic lymphocytic leukemia (CLL), since cases with mutated VH genes show significantly longer survival than unmutated cases. Recently, we reported a preferential use of the VH3-21 gene in mutated CLL and showed that mutated VH3-21 cases had an inferior overall survival compared with other mutated CLL. In order to further characterize this subset, we performed VH gene analysis in 265 CLL cases and identified 31 VH3-21 cases (11.7%); 21 cases had mutated and 10 cases unmutated VH genes. Regardless of VH gene mutation status, a poor overall survival was found in the VH3-21 cases with a median survival of 83 months. These survival data confirm that VH3-21 cases do not fit into the general prognostic grouping of mutated and unmutated CLL. A large fraction of VH3-21 cases also demonstrated unique features with shorter lengths of the third complementarity determining region (CDR3) and CDR3s with highly homologous amino acid sequences. Furthermore, the VH3-21 cases showed a striking dominance of λ light chain expression, and analysis of the Igλ gene rearrangements revealed highly restricted use of the Vλ2-14/Jλ3 genes in the majority of cases. Taken together, our new findings strengthen the suggestion that VH3-21–using cases comprise a new CLL entity, irrespective of VH gene mutation status, and implicate that a common antigen epitope, perhaps of pathogenic significance, is recognized by the highly homologous VH3-21/Vλ2-14 Ig molecules expressed in individual tumors.

Description: Telomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.

Description: Abstract 794 Introduction/Purpose: The optimal treatment schedule and best order of therapies are not well established for patients (pts) with indolent lymphoma. The aim of this trial was to evaluate the effect of adding interferon-alpha (IFN) to first-line rituximab (R) monotherapy, with extended dosing, in pts with CD20+indolent lymphoma and to define pts with no need of initial chemotherapy. Patients and methods: Pts with symptomatic, advanced indolent lymphoma (previously untreated or at first relapse after a short course of chlorambucil) were randomized to R (MabtheraR) 375 mg/m2 once-weekly for 4 consecutive weeks or R with 5 weeks IFN (Roferon-AR) as priming. Patients achieving either a complete response (CR), partial response (PR) or a minor response (MR) at evaluation 6 weeks after last R in this first cycle, were planned to receive a second cycle with four infusions of R alone or combined with IFN, according to the initial randomization. Primary endpoint was time to treatment failure (TTF), defined as the time period from randomization to one of the following events: progressive disease during treatment, death of any cause or initiation of new therapy. Results: In total, 313 patients were randomized. The median age was 59 years, 51% were females, 90% Ann Arbor stage III or IV and 31% showed elevated LDH. The clinical characteristics were well-balanced between the treatment groups. Pathology review showed 127 follicular lymphoma (FL) grade I, 110 grade II and 9 grade IIIA. In total, 4 pts in each arm did not fulfill inclusion criteria: 5 DLBCL/ transformed, 2 MCL and one Hodgkin. Most patients were previously untreated, but 10 pts in the R group and 13 with R+IFN had had a previous response to chlorambucil and 18 and 9 had had local radiotherapy. respectively. After cycle 1, response rates among all 313 randomized pts were 8.6 % CR/CRu, 47.9 % PR, 22.4 % MR and 16.9 % of pts were considered resistant (SD/PD). In total 244 pts were qualified for cycle 2. Overall response rates after cycle 2 were 82% and 74%, in the R+IFN- and the R-group, respectively (n.s), but the CR/CRu rates were higher with the combination (41% vs 22.4%, p〈 0.01). Also pts with FLIPI 3–5 (45% of all pts) showed a deeper response with R+IFN (CR/Cru 38.0% compared to 23.1%). More patients in the combination arm improved their responses from PR/MR in cycle 1, to CR after cycle 2. In the intention–to treat (ITT) population (n=313), median time to TTF was 21 and 28 months in the R and R+IFN group, respectively. Most events consisted of initiation of new therapy including chlorambucil, COP or CHOP, but in 7 patients in the R group, relapse treatment was single R (in one case with the addition of IFN) and in the R+IFN group 10 pts had R (3 with IFN). Two pts in the R-group and 12 pts in the R+IFN group had late relapses treated with local irradiation. After a median follow-up time of 60.7 months, for surviving pts, 35 % of the ITT patients were still event-free with 90% survivors, but with no difference between the treatment groups. Patients with FL grade II and IIIA showed a longer TTF than pts with grade I (p=0,05). Conclusion: This randomized phase III trial demonstrates that extended rituximab therapy is safe and effective as first-line therapy in patients with symptomatic low-grade B-cell lymphoma, with improved responses and a delayed time to early failure if combined with IFN. The long term FU suggests that more than 1/3 of this patient population does not need initial chemotherapy, but predictive markers for response to R and new biological combinations are needed. Disclosures: Kimby: Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 3565 Enteropathy-associated T-cell lymphoma (ETCL) is a rare lymphoma often, but not always, associated with celiac disease and characterized by poor prognosis when treated with conventional chemotherapy. In previous studies long-term survival has been achieved in only 10–20% of the patients. Limited data is available on the feasibility and efficacy of intensive induction chemotherapy followed by autologous stem transplantation (ASCT) in this rare lymphoma entity. We therefore specifically analysed the outcome of ETCL patients included in a large prospective phase II study (NLG-T-01) performed by the Nordic Lymphoma Group. The NLG-T-01 study included 160 patients with systemic alk-negative peripheral T-cell lymphoma over the period 2002–2007. The patients received CHOEP-14 × 6 followed by ASCT after BEAM or BEAC in responsive patients. The study included altogether 21 patients (13 %) with ETCL. There were 16 males and 5 females with a median age of 55 years (32-65) at diagnosis. Eighteen patients (86 %) had advanced disease, three patients (14 %) had a bulky tumour, nine patients (43 %) presented with B symptoms and four (19%) with elevated serum lactate dehydrogenase. Response status after three and six courses was CR or CRu in 67 % patients. Fourteen patients (67 %) received BEAM or BEAC supported by blood stem cell graft (median number of stem cells infused 5.4 × 106/kg). Of these, 6 patients relapsed with a median of 219 days from ASCT. Of the 7 patients (33%), who did not reach ASCT because of refractory/progressive disease, 5 died early due to lymphoma. At a median follow-up of 45 months, 10 patients (45 %) are alive. The progression-free survival is 40 %. One patient (5%) died due to early transplant-related cause (disseminated candidiasis). In this prospective study, intensive induction chemotherapy followed by ASCT was feasible in the majority of younger patients with EATL. In a subset of patients, who should clinically and biologically be further characterized, long-term outcome seems promising when compared to historical controls. Whether addition of other chemotherapeutic agents, antibodies such as alemtuzumab or other biologicals may further improve long-term outcome remains to be studied. Disclosures: No relevant conflicts of interest to declare.

Description: Systemic PTCL, with the exception of alk-positive anaplastic large cell lymphoma (ALCL), have a poor prognosis. ASCT has been shown to have a favourable impact on relapsed PTCL. Therefore, the NLG designed a prospective multicenter phase II study to evaluate the impact of a dose-intensified induction schedule (6 courses of two-weekly CHOEP) consolidated in 1st PR/CR with high-dose therapy (BEAM) followed by ASCT in previously untreated systemic PTCL. This is the largest prospective PTCL-specific trial published so far. Newly diagnosed non-primary cutaneous PTCL cases aged 18–67 yrs were eligible for enrollment. Cases of alk-positive ALCL were excluded. From Oct 2001 to Feb 2006, 99 histologically confirmed PTCL cases were included in the study: PTCL unspecified (n=41), alk-neg ALCL (n=24), AILT (n=15), enteropathy-type (n=12), panniculitis-like (n=3), T/NK nasal-type (n=2), hepatosplenic (n=2). The M/F ratio was 1.8 and the median age 55 yrs (range 20–67 yrs). Although almost 2/3 of the cases presented with advanced-stage disease (62%), B-symptoms (61%) and/or elevated s-LDH (63%), the majority of them (65%) had a good performance score (WHO 0–1) at diagnosis. Of the 77 patients, where information was available for all 6 induction courses, 68 (88%) were in CR (31) or PR (37) after the 3rd and 66 (86%) after the 6th course. A total of 58 patients (75%) went through ASCT indicating that at least a fourth of this younger patient cohort has a primary refractory disease and fails therapy before reaching the transplant. Treatment-related toxicity after both induction and high-dose treatment was manageable. Of the 58 transplanted patients, 50 (86%) were still in remission at re-evaluation short after transplant. In 39 patients follow-up data one year post-transplant were available: 30 are still in CR and 9 have relapsed, suggesting that post-transplant relapses probably account for another 25% of the original patient cohort. In conclusion, the present data indicate that a time- and dose-intensified schedule is feasible and effective in previously untreated systemic PTCL. Continuous remissions are not uncommon, but a longer follow-up is needed to further characterize long-term remission rates and evaluate their impact on time-to-treatment failure and overall survival.

Description: Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC+). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC+ rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC− DLBCL patients, the MYC+ DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC+ DLBCL patients than those in the MYC− DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC+ DLBCL patients have a significant inferior prognosis than MYC− DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.

Description: Recent studies on the immunoglobulin variable heavy chain (IgVH) genes have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists of at least 2 clinical entities with either somatically mutated or unmutated VH genes. We have analyzed the VH gene mutation status and VH gene usage in 119 B-CLL cases and correlated them to overall survival. A novel finding was the preferential use of the VH3-21 gene in mutated cases, whereas biased VH1-69 gene usage was found in unmutated cases as previously reported. Interestingly, the subset of mutated cases using the VH3-21 gene displayed distinctive genotypic/phenotypic characteristics with shorter average length of the complementarity determining region 3 and clonal expression of λ light chains. In addition, this mutated subset showed significantly shorter survival than other mutated cases and a similar clinical course to unmutated cases. We therefore suggest that B-CLL cases with mutated VH3-21 genes may constitute an additional entity of B-CLL.

Description: Abstract 3566 Primary systemic T-cell lymphoma of anaplastic large cell type (ALCL) is an aggressive and predominantly nodal subtype of lymphoma, further subdivided based on expression of the ALK-protein, with ALK-pos ALCL occurring predominantly in younger patients and associated with a favourable prognosis. ALK-neg ALCL is believed to carry a prognosis similar to that of other nodal peripheral T-cell lymphomas and previous studies have shown long-term survival rates below 50%. There is retrospective data suggesting a benefit from ASCT in first-line treatment of this lymphoma subtype. We analyzed the outcome of ALK-neg ALCL patients included in a prospective phase II trial, NLG-T-01, conducted by the Nordic Lymphoma Group. The NLG T-01 trial enrolled 160 patients aged 18–67 years from the Nordic countries with systemic ALK-neg peripheral T-cell lymphoma within the period 2002–2007. The treatment schedule consisted of 6 courses of CHOEP-14 followed by ASCT (BEAM or BEAC) in responding patients. Patients 〉60 years received CHOP-14 as induction. Altogether, the trial included 31 patients with ALK-neg ALCL (19% of the study population). Median age was 56 years (22-65) with a male:female ratio of 2.4. Stage III-IV was found in 18 patients (58%), B-symptoms in 19 patients (61%) and 6 patients (19%) had a bulky lesion (〉10cm). Pre-therapeutic serum lactate dehydrogenase was elevated in 18 patients (58%) and performance score was 2–4 in 10 patients (32%). After 3 and 6 courses of chemotherapy, response status was CR or CRu in 29% and 58% of the patients, respectively. In total, 24 out of 31 patients (77%) underwent BEAM/BEAC therapy followed by ASCT. Four patients did not respond or had disease progression during induction chemotherapy. The remaining 3 patients did not undergo ASCT for other reasons (mobilization failure, lung insufficiency, patient decision, respectively). Overall response rate after ASCT was 74% for the entire initial population and 96% for those undergoing ASCT. Median follow-up was 45 months. Six patients relapsed after ASCT. There was a total of nine deaths (29%): six due to lymphoma, two due to toxicity and one from second malignancy (colon cancer). With a median follow-up of 45 months, 3-year overall and progression-free survival values were 73% and 64%, respectively. Intensive chemotherapy followed by ASCT was feasible in the majority of the patients included in this prospective trial. Long-term outcome appears promising when compared to previously published data, with the survival curve suggesting a plateau. In ASCT eligible patients, intensive induction chemotherapy consolidated by upfront ASCT is an effective treatment that yields outcome results at least as good as those obtained in age-comparable patients with diffuse large B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.